Substituted imidazoles and their use

ABSTRACT

The invention provides compounds of the formula: ##STR1## wherein each of R 1 , R 2  and R 3 , which can be the same or different, is hydrogen, chloro, bromo, fluoro, methyl, ethyl, methoxy, amino, hydroxy or nitro; R 4  is hydrogen or alkyl of 1 to 7 carbon atoms; and n is 0-3; and their non-toxic pharmaceutically acceptable acid addition salts. These compounds exhibit valuable pharmacological activity and are useful in the treatment of mammals, e.g. as anti-hypertensive, β-blocking and anti-thrombotic agents. Furthermore the compounds have remarkable antimicrobial activity. The compounds may be made by a variety of methods and may be incorporated in pharmaceutical compositions also comprising a compatible pharmaceutically acceptable carrier.

DESCRIPTION

The present invention relates to substituted imidazole derivatives andtheir non-toxic, pharmaceutically acceptable acid addition salts, andtheir preparation, to pharmaceutical compositions containing the same,and to their use.

The imidazole derivatives of the present invention have the generalformula: ##STR2## wherein each of R₁, R₂ and R₃, which can be the sameor different, is hydrogen, chloro, bromo, fluoro, methyl, ethyl,methoxy, amino, hydroxy or nitro; R₄ is hydrogen or an alkyl radical of1 to 7 carbon atoms; and n is an integer from 0-3.

The non-toxic pharmaceutically acceptable acid addition salts of thesecompounds are also within the scope of the invention.

The compounds of the formula (I) form acid addition salts with bothorganic and inorganic acids. They can thus form many pharmaceuticallyusable acid addition salts, such as, for instance, chlorides, bromides,sulfates, nitrates, phosphates, sulfonates, formates, tartrates,maleates, citrates, benzoates, salicylates, ascorbates and the like.

The invention includes within its scope pharmaceutical compositionscomprising at least one of the compounds of formula (I) or a non-toxic,pharmaceutically acceptable acid addition salt thereof, and a compatiblepharmaceutically acceptable carrier therefor.

The present invention provides, for example, the following specificcompounds of formula (I):

4-[3-(2',6'-dimethylphenyl)-1-propenyl]-imidazole

4-[2-(2',3'-dimethylphenyl)-ethenyl]-imidazole

4-[2-(2',6'-dimethylphenyl)-ethenyl]-imidazole

4-[5-(2',6'-dimethylphenyl)-1-pentenyl]-imidazole

4-[2-(2',6'-dichlorophenyl)-ethenyl]-imidazole

4-[3-(2',4'-dimethylphenyl)-1-propenyl]-imidazole

4-[3-(2',3'-dimethylphenyl)-1-propenyl]-imidazole

4-(3-phenyl-1-propenyl)-imidazole

4-[3-(2'-methylphenyl)-1-propenyl]-imidazole

4-[3-(3'-methylphenyl)-1-propenyl]-imidazole

4-[3-(4'-methylphenyl-1-propenyl]-imidazole

4-[3-(2',4',6'-trimethylphenyl)-1-propenyl]-imidazole

4-[3-(4'-ethylphenyl)-1-propenyl]-imidazole

4-[2-(3',4'-dihydroxyphenyl)-ethenyl]-imidazole

4-[5-(2'-methylphenyl)-1-pentenyl]-imidazole

4-[4-(2',6'-dichlorophenyl)-1-butenyl]-imidazole

4-[2-(2',6'-dichlorophenyl)-ethenyl]-5-methyl-imidazole

4-[2-(2'-chlorophenyl)-ethenyl]-5-methyl-imidazole

4-[3-(3'-methoxyphenyl)-1-propenyl]-imidazole

4-[2-(2',6'-dimethylphenyl)-ethenyl]-5-methyl-imidazole

4-[2-(2',4',6'-trimethylphenyl)-ethenyl]-imidazole

4-[2-(2',3'-dichlorophenyl)-ethenyl]-imidazole

4-[2-(2',3'-dimethylphenyl)-ethenyl]-5-methyl-imidazole

4-[2-(2',6'-diethylphenyl)-ethenyl]-imidazole

4-[2-(2',3'-diethylphenyl)-ethenyl]-imidazole

4-[2-(2',6'-dimethoxyphenyl)-ethenyl]-imidazole

4-[2-(2',6'-difluorophenyl)-ethenyl]-imidazole

4-[2-(2',6'-dibromophenyl)-ethenyl]-imidazole

4-[3-(2',6'-dimethylphenyl)-1-propenyl]-5-methyl-imidazole

4-[3-(2',6'-diethylphenyl)-1-propenyl]-imidazole

4-[3-(2'-bromophenyl)-1-propenyl]-imidazole

4-[3-(3'-chlorophenyl)-1-propenyl]-imidazole

4-[3-(4'-chlorophenyl)-1-propenyl]-5-methyl-imidazole

4-[3-(2',6'-dichlorophenyl)-1-propenyl]-imidazole

4-[3-(2',6'-dibromophenyl)-1-propenyl]-imidazole

4-(4-phenyl-1-butenyl)-5-methyl-imidazole

4-[3-(2',3'-difluorophenyl)-1-propenyl]-imidazole

4-[3-(2',3'-dimethoxyphenyl)-1-propenyl]-imidazole

4-[3-(2',4'-dihydroxyphenyl)-1-propenyl]-imidazole

4-[3-(2'-hydroxyphenyl)-1-propenyl]-imidazole

4-[4-(2',4'-dichlorophenyl)-1-butenyl]-imidazole

4-[4-(2',6'-dimethoxyphenyl)-1-butenyl]-imidazole

4-[4-(2',3'-diethylphenyl)-1-butenyl]-imidazole

4-[4-(2',6'-dimethylphenyl)-1-butenyl]-imidazole

4-4-(2'-hydroxyphenyl)-1-butenyl]-imidazole

4-[5-(2'-bromophenyl)-1-pentenyl]-imidazole

4-[5-(2',6'-dichlorophenyl)-1-pentenyl]-imidazole

4-[5-(3'-methoxyphenyl)-1-pentenyl]-imidazole

4-[5-(2',6'-dimethylphenyl)-1-pentenyl]-5-methyl-imidazole

4-[3-(2',3'-dimethylphenyl)-1-propenyl]-5-methyl-imidazole

4-(3-phenyl-1-propenyl)-5-methyl-imidazole

4-(2-phenylethenyl)-5-methyl-imidazole

4-[3-(4'-methylphenyl)-1-propenyl]-5-methyl-imidazole

4-[3-(3'-methylphenyl)-1-propenyl]-5-methyl-imidazole

4-[2-(3',4'-dimethylphenyl)-ethenyl]-5-methyl-imidazole

4-[2-(2',5'-dimethylphenyl)-ethenyl]-5-methyl-imidazole

The compounds of the present invention have been found to possess goodantihypertensive properties. Preliminary tests have shown that they alsopossess other valuable pharmacological properties, for example,β-blocking, antithrombotic and diuretic activity. Furthermore thecompounds have proved to possess remarkable antimicrobial activity.

While all of the compounds of formula (I) have the aforementionedactivities, certain groups of the compounds remain preferred. One suchpreferred group can be represented by the structural formula: ##STR3##wherein n is the same as before; each of R'₁, R'₂ and R'₃ is hydrogen,chloro, methyl, ethyl, methoxy or hydroxy; and R'₄ is hydrogen ormethyl.

According to a feature of the invention, the compounds of formula (I)are prepared by dehydration of the corresponding imidazoles of theformula: ##STR4## wherein R₁, R₂, R₃ and R₄ are defined as before and nis 1-4. The dehydration is carried out according to known methods forinstance by refluxing the hydroxysubstituted compound in an appropriateacidic solution, e.g. concentrated hydrochloric acid. Alternatively thehydroxy-substituted imidazole can be dehydrated by heating it togetherwith anhydrous potassium hydrogen sulfate.

The compounds of formula (III) are made by a Grignard reaction in whichan imidazole aldehyde of the formula: ##STR5## wherein R₄ is defined asbefore, is reacted with an arylalkyl magnesium halide derivative of theformula: ##STR6## wherein R₁, R₂, and R₃ are defined as before, n is aninteger from 1-4 and Hal is a halogen atom.

The arylalkylmagnesium halide derivative can be, for example, anarylalkylmagnesiumbromide derivative, which is prepared by reacting thecorresponding arylalkylbromide derivative with magnesium. Suitablesolvents for the reaction include a variety of ethers, preferablytetrahydrofuran. The arylalkylmagnesiumhalide derivative is prepared inthe usual way by adding the arylalkylmagnesiumhalide derivative in asuitable solvent, e.g. tetrahydrofuran, dropwise onto magnesium turningscovered by tetrahydrofuran, at the boiling point of the reactionmixture. When the magnesium turnings have reacted, the mixture is cooledslightly and the 4-imidazole derivative is added in solid form in smallportions. After the addition, the reaction mixture is refluxed until allof the 4-imidazole derivative has reacted.

The reaction time varies between one and five hours. In the reaction, atleast two equivalents of arylalkylmagnesiumhalide are used per oneequivalent of 4-imidazolealdehyde, because the last mentioned compoundcontains active hydrogen which binds a part of the Grignard reagent.

The above described Grignard reaction utilizing a 4-imidazolealdehyde asstarting material is a surprising and new method for the synthesis ofimidazole derivatives. The process is surprising in view of theteachings of the prior art. Thus, for example, Deulofeu et al.,J.Org.Chem., 14, 1949, 915 states that 4-imidazolealdehyde does notreact with methylmagnesiumiodide, i.e., in the Grignard reaction.

Another process for the preparation of compounds of formula (I) is aWittig reaction which comprises reacting an imidazole aldehyde of theformula: ##STR7## wherein R₄ is the same as before, with anaralkylidenetriphenylphosphorane of the formula: ##STR8## wherein R₁, R₂and R₃ are the same as before and n is 0-3. Thearalkylidenetriphenylphosphoranes are preferably prepared by reactingthe corresponding aralkyltriphenylphosphonium halide of the formula:##STR9## wherein R₁, R₂ and R₃ are the same as before, n is 0-4 and Halis a halogen atom, with a basic reagent, preferably butyllithium.

The processes described above for the preparation of compounds offormula (I) result mainly in the trans isomer of the compound. The transisomer can be converted to the cis isomer according to known methods,e.g. by heating it in the presence of an acid or by irradiating it withultraviolet light.

Yet another process for the preparation of the compounds of formula (I),wherein R₄ is hydrogen or methyl, comprises reacting a compound of theformula: ##STR10## wherein R₁, R₂ and R₃ are defined as before, X is ahalogen atom or hydroxy, R₄ is hydrogen or methyl and n is 0-3 with areagent capable of converting said starting material to thecorresponding imidazole of the formula: ##STR11## Formamide ispreferably used as the reagent.

As stated herein above, the compounds of the general formula (I) andtheir non-toxic, pharmaceutically acceptable acid addition salts havevaluable pharmacological properties and have been found to possess goodanti-hypertensive activity in mammals. This activity makes theseimidazole derivatives particularly useful in the treatment of high bloodpressure. Furthermore the compounds have proved to possess remarkableantimicrobial activity. Preliminary tests have shown that they alsopossess other pharmacological properties, for example, β-blocking,antithrombotic and diuretic activity.

Administration of isomeric compounds of formula (I), their non-toxic,pharmaceutically acceptable acid salts or mixtures thereof may beachieved parenterally, intravenously or orally. Typically, an effectiveamount of the derivative is combined with a suitable pharmaceuticalcarrier. As used herein, the term "effective amount" encompasses thoseamounts which yield the desired activity without causing adverseside-effects. The precise amount employed in a particular situation isdependent upon numerous factors such as method of administration, typeof mammal, condition for which the derivative is administered, etc., andof course the structure of the derivative.

The pharmaceutical carriers which are typically employed with thederivatives of the present invention may be solid or liquid and aregenerally selected with the planned manner of administration in mind.Thus, for example, solid carriers include lactose, sucrose, gelatin andagar, while liquid carriers include water, syrup, peanut oil and oliveoil. Other suitable carriers are well-known to those skilled in the artof pharmaceutical formulations. The combination of the derivative andthe carrier may be fashioned into numerous acceptable forms, such astablets, capsules, suppositories, solutions, emulsions, and powders.

The anti-hypertensive properties of the imidazole derivatives of thepresent invention have been determined according to the followingprocedure. Sprague-Dawley rats of normal weight were first anesthetizedwith urethane. After this, the femoral artery was connected by way of apolyethylene tube with a blood pressure transducer. The test substancewas then injected into the femoral vein and the blood pressure and thepulse frequency were registered with a recorder.

The antimicrobial activity was determined in vitro according to aqualitative test for antibacterial and antifungal activity, using theagar diffusion method, against the following standard organisms:Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli, Proteusmirabilis, Pseudomonas aeruginosus, Candida albicans and Aspergillusniger.

The β-blocking activity was measured in vitro as follows: The atrium ofa guinea-pig was isolated. The inhibiting activity of the compoundagainst isoprenaline-induced chronotropic and inotropic action in theisolated atrium was measured.

The antithrombotic activity was investigated in vivo in mice as follows:The compounds to be tested were administered orally. After thisarachidonic acid was given i.v. The inhibiting activity of the testcompounds against arachidonic acid induced pulmonary thromboembolism wasinvestigated.

In a further test the antithrombotic activity was investigated in vitro.The inhibiting activity of the compounds against ADP- andcollagen-induced aggregation of thrombocytes was measured. In the testthrombocytes from a cow was used. To 1.2 ml of plasma containing 250000thrombocytes/mm³ were added 50 μl of a solution of the compound to betested. After 10 min incubation either ADP or collagen was added. Theaggregation of the thrombocytes was turbidimetrically determined atλ=605 n m.

Acute toxicity was determined by using female mice of NMRI-Strain withan age of about 7 months and weighing 30-40 g. The administration of thetest compound was i.v.

Thus, the trans isomer of the compound4-[2-(2',6'-dimethylphenyl)-ethenyl]-imidazole, which has a LD₅₀ valueof 50 mg/kg i.v. in mice was found in the blood pressure study withanesthetized rats of normal weight described above to cause aregistrable lowering of the blood pressure with a dose of 10 μg/kg i.v.With a dose of 300 μg/kg i.v., the reduction of the blood pressure was20%, and the decrease of pulse frequency was 24%. The effect wasmeasured 20 minutes after administration.

For the compound 4-[2-(2',6'-dichlorophenyl)-ethenyl]-5-methyl-imidazolehaving a LD₅₀ of 100 mg/kg i.v. in mice, a registrable lowering of theblood pressure was measured with a dose of 300 μg/kg i.v., and adecrease of pulse frequency was noticed at a dose of 1 mg/kg i.v.

A dose of 3 mg/kg i.v. caused 30% lowering of the blood pressuremeasured 20 minutes after administration.

For the compound 4-[3-(2',6'-dimethylphenyl)-1-propenyl]-imidazolehaving a LD₅₀ of 75 mg/kg i.v. in mice, a dose of 1-3 mg/kg i.v. gave a20% decrease of the blood pressure measured 20 minutes afteradministration.

For the compound 4-[3-(2',3'-dimethylphenyl)-1-propenyl]-imidazolehaving a LD₅₀ of 75 mg/kg i.v. in mice, a dose of 0.3-1 mg/kg i.v.caused a 20% decrease of the blood pressure measured 20 minutes afteradministration.

For the compound 4-[2-(2',6'-dichlorophenyl)-ethenyl]-imidazole having aLD₅₀ of 85 mg/kg i.v. in mice the lowering of the blood pressure was 25%with a dose of 1 mg/kg i.v. With the same dose, the pulse frequencydecreased with 30%. The registration was performed 20 minutes afteradministration.

In the antimicrobial test the compound4-[2-(2',6'-dichlorophenyl)-ethenyl]-imidazole was active at 1000 μg/mlagainst all standard bacterial and fungal species.

The compound 4-[2-(2'-chlorophenyl)-ethenyl]-5-methyl-imidazole having aLD₅₀ of 85 mg/kg i.v. in mice was active at 1000 μg/ml against all thebacterial species, but not against the fungi.

The compound 4-[2-(2',6'-dichlorophenyl)-ethenyl]-5-methyl-imidazole wasactive at 1000 μg/ml against all the bacterial species and Candidaalbicans, but was inactive against Aspergillus niger.

The compound 4-[5-(2',6'-dimethylphenyl)-1-pentenyl]-imidazole having aLD₅₀ of 40 mg/kg i.v. in mice was active at 100 μg/ml against E. coliand Staph. aureus. At 1000 μg/ml it was active against all otherbacterial and fungal species.

In the β-blocking activity test, the compound4-[2-(2'-chlorophenyl)-ethenyl]-5-methyl-imidazole gave at aconcentration of 1 μg/ml a 67 percent inhibition of isoprenaline-inducedchronotropic effect.

The compound 4-[5-(2',6'-dimethylphenyl)-1-pentenyl]-imidazole caused a57 percent inhibition of isoprenaline induced chronotropic effect at aconcentration of 1 μg/ml.

In the antithrombotic activity test (in vivo), the compound4-[2-(2'-chlorophenyl)ethenyl]-5-methyl-imidazole protected 4 of 5 micefrom arachidonic acid-induced pulmonary thromboembolism at a dose of 10mg/kg p.o.

According to the in vitro test for antithrombotic activity the compound4-[3-(2',3'-dimethylphenyl)-1-propenyl]-imidazole inhibited thecollagen-induced thrombocyte aggregation completely and the ADP-inducedaggregation clearly. LD₅₀ =75 mg/kg in mice.

The compound 4-[2-(2',6'-dichlorophenyl)-ethenyl]-imidazole gave thefollowing diuretic effect:

    ______________________________________                                        Dosage, mg/kg     diuretic effect, % (5h)                                     ______________________________________                                        0.005             128                                                         0.05              132                                                         0.5               135                                                         ______________________________________                                    

The diuretic effect was studied in rats by collecting the urine outputduring 0-5 hours after i.p. injection of the compound. Before the testthe rats were fasting overnight and got 10 ml water p.o. immediatelybefore the injection.

In the Examples below, where 1_(H) -NMR or 13_(C) -NMR spectrum shiftsare presented, the NMR spectra were determined with a Brucker WB 80 DSapparatus using tetramethylsilane or 3-(trimethylsilyl)-propansulfonacidsodium salt standard, from which the presented chemical shifts (∂,ppm)are tabulated. The letters s, d, t and m are used to indicate a singlet,doublet, triplet or multiplet, respectively. In the same connection, thenumber of hydrogen atoms is also stated. In some of the examples thecoupling constants J (H_(z)) are given for protons typical for trans andcis isomers. The compounds which are indicated as bases are tested indeuterium methanol, deuterium acetone or deuterium chloroform, while thevalues for compounds which are indicated as hydrochlorides weredetermined in deuterium oxide.

The mass-spectra were determined with a Perkin-Elmer RMU apparatus usingdirect inlet system. The temperature employed was the lowest temperatureneeded for the evaporation of the compound as base. In the examples thestrongest and the most essential fragment-ions from a structuralviewpoint are given as m/e values. In parenthesis is given the intensityof the fragment-ion in relation to the main peak.

The following Examples illustrate the invention, in which the productsprincipally occur as trans isomers (if there is no mention about isomerrelationships).

EXAMPLE 1 4-[3-(2',6'-Dimethylphenyl)-1-hydroxypropyl]-imidazole

4.8 g of dry magnesium turnings are covered with 100 ml of drytetrahydrofuran (THF). The mixture is heated to boiling and a solutionof 42.6 g of 2-(2',6'-dimethylphenyl)-1-bromoethane in 100 ml of drytetrahydrofuran is added dropwise at such a rate that gentle refluxingis maintained. After the addition is complete, the reaction mixture isrefluxed for an additional 30 minutes.

The reaction mixture is cooled to 50° C. and 7.0 g of4-imidazolealdehyde is added slowly in small portions. After theaddition is complete, the mixture is refluxed for 5 hours. Then thereaction mixture is cooled and poured into 200 ml of cold watercontaining 20 ml of concentrated hydrochloric acid. Part of thetetrahydrofuran is distilled off to give a smaller volume and thetetrahydrofuran is replaced with water. The mixture is washed twice with50 ml portions of chloroform. The aqueous layer is made alkaline withsodium hydroxide solution (pH about 8). The precipitate which forms iswashed with water and added to 100 ml of 4 N NaOH solution and themixture is stirred vigorously for one hour. The precipitate is filtered,washed several times with water and dried. The crude product isrecrystallized from a mixture of water and ethanol to give 10.1 g of aproduct melting at 157°-158° C.

¹ H-NMR: 2.3 (m, 2H), 2.6 (s, 6H), 3.0 (m, 2H), 5.15 (t, 1H), 5.45 (s,2H), 7.25 (s, 3H), 7.35 (s, 1H), 8.0 (s, 1H).

MS: 230 (21%), 212 (20%), 197 (13%), 133 (11%), 124 (7%), 119 (18%), 118(23%), 117 (18%), 115 (11%), 111 (98%) 98 (100%), 97 (69%), 95 (8%), 93(7%), 91 (21%), 82 (27%), 81 (10%).

EXAMPLE 2 4-[3-(2',6'-Dimethylphenyl)-1-propenyl]-imidazole

10 g of 4-[3-(2',6-dimethylphenyl)-1-hydroxypropyl]-imidazole isrefluxed in 100 ml of concentrated hydrochloric acid for 10 hours. Aftercooling, the solution is extracted with chloroform. The combinedchloroform extracts are washed with 10 percent sodium hydroxidesolution, then with water, dried and evaporated to dryness. The residuewhich is crude product is purified further by column chromatographyusing a Merck's reversed phase column, eluting the column with methanol.The melting point of the product is 162°-168° C. (as hydrochloride fromethyl acetate).

¹ H-NMR (HCl-salt): trans isomer: 2.0 (s, 6H), 3.2 (d, 2H), 4.7 (s, 2H),5.7 (d, 1H J: 16.5 H_(z), typical for trans isomer), 6.05 (m, 1H), 6.6(s, 1H), 6.7 (s, 3H), 8.4 (s, 1H)

EXAMPLE 3 4-[2-(2',6'-Dichlorophenyl)-ethenyl]-imidazole

6.5 g of 4-[2-(2',6'-Dichlorophenyl)-1-hydroxyethyl]-imidazole is mixedwith 25 g of anhydrous potassium hydrogen sulfate and the mixture iswarmed on oil bath at 150°-155° C. for 3 hours. The mixture is thencooled and 30 ml of methanol are added. The mixture is stirred andfiltered. The cake is washed with methanol, the methanol filtrates arecombined and evaporated to dryness. The residue is dissolved inmethylene chloride, which is washed first with a dilute sodium hydroxidesolution and then with water. Then it is evaporated to dryness. Theresidue is dissolved in isopropanol and the pH is adjusted to 4 withHCl-ethylacetate. The hydrochloride of the product is filtered andwashed with ethylacetate. The hydrochloride salt melts at 207°-212° C.The free base is liberated from the hydrochloride in water with sodiumhydroxide. The melting point of the base is 156°-157° C.

EXAMPLE 4 4-[2-(2',3'-Dimethylphenyl)-ethenyl]-imidazole

51.5 g of 2,3-dimethylbenzyl-triphenylphosphonium chloride is dissolvedin 300 ml of tetrahydrofuran. The mixture is warmed to 40° C. Then 78 mlof a hexane solution of butyl lithium (butyl lithium concentration 1,66mol/l) are added in a nitrogen atmosphere during 1-2 hours at such arate that a temperature of 40°-50° C. is maintained with gentle cooling.After the addition is complete, the mixture is stirred at about 60° C.for another 2 hours. The reaction mixture is then cooled to 20° C. afterwhich 9.6 g of 4-imidazolealdehyde is added in small portions. Themixture is stirred at 60° C. for 5 hours. The reaction mixture is thencooled to about 20° C. and 300 ml of water is added. Then the mixture isevaporated to a smaller volume, after which water is added again toreplace the evaporated solvents. The pH is adjusted to 3-4 with HCl andthe mixture is washed with toluene. The aqeuous layer is made alkaline,and the precipitate, which contains the crude product, is removed byfiltration, washed and dried. The product is converted into thehydrochloride in toluene by adding HCl-ethylacetate. The hydrochloride,after recrystallization from water, melts at 204°-207° C. The base,which is liberated from the hydrochloride in water, has a melting pointof 179°-183° C.

¹ H-NMR (trans isomer): 2.3 (s, 6H), 3.75 (s, 1H), 6.8 (d, 1H. J: 16.1H_(z), typical for trans isomer), 7.0-7.57 (m, 6H).

EXAMPLE 5 4-[2-(2',6'-Dimethylphenyl)-ethenyl]-imidazole

The procedure of example 4 is repeated, except that2,6-dimethylbenzyltriphenylphosphonium chloride is used as startingmaterial in place of 2,3-dimethylbenzyltriphenylphosphonium chloride.Almost pure trans isomer is obtained as reaction product. This isconvertend to the hydrochloride in ethylacetate by addingHCl-ethylacetate. The melting point of the hydrochloride is 208°-215° C.The base, which is liberated from the hydrochloride in water with sodiumhyroxide, has a melting point of 123°-130° C.

The trans isomer is converted to the cis isomer by irradiating theformer with ultraviolet light for 2 days in toluene solution. Thisresults in a mixture containing about 30% of the trans isomer and about70% of the cis isomer. The isomers are separated by liquidchromatography, eluating with a mixture of methanol and chloroform. Thetrans isomer (HCl-salt) has a melting point of 213°-217° C. The cisisomer (HCl-salt) melts at 237°-240° C.

¹ H-NMR (trans isomer): 2.3 (s, 6H), 5.6 (s, 1H), 6.45 (d, 1H, J: 16.8H_(z), typical for trans isomer), 6.9-7.2 (m, 5H), 7.6 (s, 1H).

¹³ C-NMR (trans isomer): 115.13 (d), 117.67 (d), 127.66 (d), 128.11 (d),132.14 (d), 132.44 (s), 133.38 (d), 134.86 (s), 136.20 (s).

¹ H-NMR (cis isomer): 2.2 (s, 6H), 6.3 (d, 1H. J: 11.8 H_(z), typicalfor cis isomer), 6.4 (s, 1H), 6.6 (d, 1H. J: 11.8 H_(z), typical for cisisomer), 7.1 (s, 3H), 7.3 (s, 1H), 9.8 (s, 1H).

¹³ C-NMR (cis isomer): 114.91 (d), 116.55 (d), 128.20 (d), 128.20 (d),130.44 (s), 131.96 (d), 134.62 (d), 134.83 (s), 135.35 (s).

In the examples 6-14 the procedure of example 3 is repeated, except thatin place of 4-[2-(2',6'-dichlorophenyl)-1-hydroxyethyl]-imidazole isused the corresponding 4-[(substitutedphenyl)-1-hydroxyalkyl]-imidazole.

EXAMPLE 6 4-[5-(2',6'-Dimethylphenyl)-1-pentenyl]-imidazole

M.p. of the hydrochloride 172°-180° C.

EXAMPLE 7 4-[3-(2',4'-Dimethylphenyl)-1-propenyl]-imidazole

M.p. 158°-165° C. (from diisopropylether).

EXAMPLE 8 4-[3-(2',3'-Dimethylphenyl)-1-propenyl]-imidazole

M.p. of the hydrochloride 172°-182° C. (from isopropanol-ether).

EXAMPLE 9 4-(3-Phenyl-1-propenyl)-imidazole

M.p. of the hydrochloride 148°-153° C. (from isopropanol).

EXAMPLE 10 4-[3-(2'-Methylphenyl)-1-propenyl]-imidazole

M.p. of the hydrochloride 174°-178° C. (from isopropanol).

EXAMPLE 11 4-[3-(4'-Methylphenyl)-1-propenyl]-imidazole

M.p. of the hydrochloride 179°-184° C. (from isopropanol).

EXAMPLE 12 4-[3-(2',4',6'-Trimethylphenyl)-1-propenyl]-imidazole

M.p. of the base 74°-84° C.

EXAMPLE 13 4-[3-(4'-Ethylphenyl)-1-propenyl]-imidazole

M.p. of the base 70°-74° C.

EXAMPLE 14 4-[5-(2'-Methylphenyl)-1-pentenyl]-imidazole

¹ H-NMR (HCl-salt): 1.8 (m, 2H), 2.2 (s, 3H), 2.6 (m, 4H), 5.0 (s, 2H),5.8-6.3 (m, 2H), 7.1 (m, 5H), 8.6 (s, 1H).

In the examples 15-22 the procedure of example 3 is repeated, exceptthat in place of 4-[2-(2',6'-dichlorophenyl)-1-hydroxyethyl]-imidazoleis used the corresponding 4-[(substitutedphenyl)-1-hydroxyalkyl]-5-methyl-imidazole.

EXAMPLE 15 4-(3-phenyl-1-propenyl)-5-methyl-imidazole

M.p. of the hydrochloride 202°-205° C.

EXAMPLE 16 4-(2-phenylethenyl)-5-methyl-imidazole

M.p. of the hydrochloride 250° C.

EXAMPLE 17 4-[2-(2',3'-dimethylphenyl)-ethenyl]-5-methyl-imidazole

M.p. of the base 204°-206° C.

EXAMPLE 18 4-[2-(2',6'-Dichlorophenyl)-ethenyl]-5-methyl-imidazole

M.p. of the hydrochloride 104°-109° C. M.p. of the base 80°-86° C.

EXAMPLE 19 4-[2-(2'-Chlorophenyl)-ethenyl]-5-methyl-imidazole

M.p. of the hydrochloride 230°-234° C. (from isopropanol-ether).

EXAMPLE 20 4-[2-(2',5'-dimethylphenyl)-ethenyl]-5-methyl-imidazole

M.p. of the hydrochloride 204°-208° C.

EXAMPLE 21 4-[2-(3',4'-dimethylphenyl)-ethenyl]-5-methyl-imidazole

M.p. of the hydrochloride 214°-226° C. (the products include about 10%of the cis isomer).

EXAMPLE 22 4-[3-(4'-methylphenyl)-1-propenyl]-5-methyl-imidazole

M.p. of the hydrochloride 215°-216° C.

EXAMPLE 23 4-[3-(3'-Methoxyphenyl)-1-propenyl]-imidazole

The procedure of example 4 is repeated except that,2-(3-methoxyphenyl)-ethyltriphenylphosphonium chloride is used in placeof 2,3-dimethylbenzyltriphenylphosphonium chloride. M.p. of thehydrochloride 128°-132° C.

EXAMPLE 24 4-[2-(2',6'-dimethylphenyl)-ethenyl]-5-methyl-imidazole

The procedure of example 3 is repeated except that4-[2-(2',6'-dimethylphenyl)-1-hydroxyethyl]-5-methyl-imidazole is usedin place of 4-[2-(2',6'-dichlorophenyl)-1-hydroxyethyl]-imidazole.

M.p. of the hydrochloride 207°-210° C.

¹ H-NMR: 2.415 (s, 6H), 2.441 (s, 3H), 5.03 (s, 2H), 6.51 (d, 1H), 7.14(s, 3H), 7.24 (d, 1H), 8.78 (s, 1H)

We claim:
 1. A substituted imidazole of the formula: ##STR12## whereineach of R₁, R₂ and R₃, which can be the same or different, is hydrogen,chloro, bromo, fluoro, methyl, ethyl, methoxy, amino, hydroxy or nitro;R₄ is hydrogen or an alkyl radical of 1 to 7 carbon atoms; and n is aninteger from 0-3, and its non-toxic pharmaceutically acceptable acidaddition salts.
 2. A compound according to claim 1, wherein each of R₁,R₂ and R₃, which can be the same or different, is hydrogen, chloro,methyl, ethyl, methoxy, or hydroxy.
 3. A compound according to claim 1,wherein R₁ is hydrogen, chloro, methyl, ethyl or methoxy and each of R₂and R₃, which can be the same or different, is chloro, methyl, ethyl ormethoxy.
 4. A compound according to claim 1, 2, or 3, wherein R₄ ishydrogen or methyl.
 5. 4-[3-(2',6'-Dimethylphenyl)-1-propenyl]-imidazoleand its non-toxic pharmaceutically acceptable acid addition salts. 6.4-[2-(2',3'-Dimethylphenyl)-ethenyl]-imidazole and its non-toxicpharmaceutically acceptable acid addition salts. 7.4-[2-(2',6'-Dimethylphenyl)-ethenyl]-imidazole and its non-toxicpharmaceutically acceptable acid addition salts. 8.4-[5-(2',6'-Dimethylphenyl)-1-pentenyl]-imidazole and its non-toxicpharmaceutically acceptable acid addition salts. 9.4-[2-(2',6'-Dichlorophenyl)-ethenyl]-imidazole and its non-toxicpharmaceutically acceptable acid addition salts. 10.4-[3-(2',4'-Dimethylphenyl)-1-propenyl]-imidazole and its non-toxicpharmaceutically acceptable acid addition salts. 11.4-[3-(2',3'-Dimethylphenyl)-1-propenyl]-imidazole and its non-toxicpharmaceutically acceptable acid addition salts. 12.4-[2-(2',6'-Dichlorophenyl)-ethenyl]-5-methylimidazole and its non-toxicpharmaceutically acceptable acid addition salts. 13.4-[2-(2'-Chlorophenyl)-ethenyl]-5-methylimidazole and its non-toxicpharmaceutically acceptable acid addition salts.
 14. A pharmaceuticalcomposition useful for treating hypertension comprising ananti-hypertensive effective amount of a substituted imidazole as claimedin claim 1 or a non-toxic pharmaceutically acceptable acid addition saltthereof in association with a compatible pharmaceutically acceptablecarrier.
 15. A pharmaceutical composition useful for killing microbeswhich comprises an anti-microbially effective amount of a substitutedimidazole as claimed in claim 1 or a non-toxic pharmaceuticallyacceptable acid addition salt thereof in association with a compatiblepharmaceutically acceptable carrier.
 16. A pharmaceutical compositionuseful for treating thrombosis which comprises an anti-thromboticallyeffective amount of a substituted imidazole as claimed in claim 1 or anon-toxic pharmaceutically acceptable acid addition salt thereof inassociation with a compatible pharmaceutically acceptable carrier.
 17. Apharmaceutical composition useful for blocking β-receptors in a subjectin whom such block may be beneficial comprising an amount effective toblock said β-receptors of a substituted imidazole as claimed in claim 1or a non-toxic pharmaceutically acceptable acid addition salt thereof inassociation with a compatible pharmaceutically acceptable carrier.
 18. Acomposition as claimed in claim 14, 15, 16, or 17, in which the carrieris a solid.
 19. A composition as claimed in claim 14, 15, 16, or 17 inthe form of a tablet, capsule, suppository, sterile solution, emulsionor powder.
 20. Method of treating hypertension which comprisesadministering to a subject suffering therefrom or subject thereto aneffective amount of a substituted imidazole as claimed in claim 1 or anon-toxic pharmaceutically acceptable acid addition salt thereof. 21.Method of killing microbes which comprises exposing said microbes to aneffective toxic amount of a substituted imidazole as claimed in claim 1or a non-toxic pharmaceutically acceptable acid addition salt thereof.22. Method of treating thrombosis which comprises administering to asubject suffering therefrom or subject thereto an effective amount of asubstituted imidazole as claimed in claim 1 or a non-toxicpharmaceutically acceptable acid addition salt thereof.
 23. Method ofblocking β-receptors in a subject in whom such block may be beneficialwhich comprises administering to such subject an effective amount of asubstituted imidazole as claimed in claim 1 or a non-toxicpharmaceutically acceptable acid addition salt thereof.